Combined Ketamine and Cognitive-Behavioral Therapy: Leveraging Metaplasticity to Enhance Treatment Outcomes

Over the past two decades, ketamine has emerged as a rapid-acting antidepressant, especially among patients with treatment-resistant depression. As an N-methyl-d-aspartate glutamate receptor antagonist, ketamine has reshaped the understanding of the underlying neurobiological mechanisms of depression treatment. Ketamine induces a transient state of enhanced neuroplasticity and likely potentiates metaplasticity-the brain's increased capacity to undergo future plastic changes. These effects suggest a posttreatment window during which patients are more cognitively flexible and responsive to other interventions. This theoretical framework has led to increasing interest in pairing ketamine with psychotherapies, such as cognitive-behavioral therapy (CBT), to enhance response and reduce relapse after ketamine treatment. This combined approach differs conceptually from ketamine-assisted psychotherapy, which is modeled after psychedelic-assisted therapy and emphasizes the consciousness-altering experience of ketamine as being integral to the therapeutic process. Multiple early studies suggest that CBT or other cognitive therapies delivered after ketamine treatment may leverage the neurobiological changes and cognitive flexibility ketamine induces to produce an enhanced and more durable antidepressant effect. However, the evidence remains limited, and critical parameters such as optimal timing and structure for combined treatment remain undefined. This review summarizes the theoretical rationale for and emerging empirical evidence supporting the integration of ketamine or esketamine with cognitive therapies. The authors evaluate recent clinical trials and highlight gaps in the literature, and conclude with a proposed framework for interventional psychiatrists seeking to incorporate CBT into ketamine-based treatment programs.